Abstract Homeostatic signaling systems operate as protective mechanisms at the level of individual synapses, neurons, and neural circuits to stabilize brain function and animal behavior. Defective homeostatic regulation causes synapse and neural network instability, which is associated with multiple chronic neural disorders, such as epilepsy, autism and Alzheimer's Disease. Glia are key players that control many different aspects of neural development and synaptic function and are increasingly linked to neurodevelopmental and neurodegenerative pathology. However, virtually nothing is known about whether and how glial signaling is involved in modulating presynaptic neurotransmitter release in synaptic homeostasis. Our preliminary data in Drosophila suggest that impairment of glial signaling completely abolishes presynaptic homeostasis when the nervous system is challenged by acute or long-term synaptic perturbations. We demonstrate that glia respond to chronic inhibition of postsynaptic glutamate receptor sensitivity by modulating their histone acetylation codes. Through a genetic screen in Drosophila, we identified genes that function specifically in glia for the induction and sustained expression of presynaptic homeostasis. Our preliminary data emphasize the importance of epigenetic mechanism-mediated glial signaling in stabilizing synaptic function. We propose to fill the mechanistic gap of understanding the glial signaling in stabilizing the brain function. We will systematically study how the interactions between glia and neuron affect synaptic transmission and synapse stability by using a wide array of genetic, molecular, cellular, electrophysiological, imaging and bioinformatic approaches. We will further extend our studies to mouse hippocampal cultures to examine how astrocyte-expressed epigenetic regulators modulate presynaptic calcium influx, neurotransmitter vesicle pool size and neurotransmitter release. Understanding the function of glial-derived molecules in stabilizing the nervous system confronting chronic harmful stimuli will benefit the development of new treatments and potential therapeutics for neural disorders caused by synapse instability.